VCV000040701.15 - ClinVar

NM_005633.4(SOS1):c.2197A>T (p.Ile733Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005633.4(SOS1):c.2197A>T (p.Ile733Phe)

Variation ID: 40701 Accession: VCV000040701.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p22.1 2: 39012319 (GRCh38) [ NCBI UCSC ] 2: 39239460 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 24, 2015	Feb 14, 2024	Mar 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005633.4:c.2197A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005624.2:p.Ile733Phe	missense
NM_001382394.1:c.2176A>T	NP_001369323.1:p.Ile726Phe	missense
NM_001382395.1:c.2197A>T	NP_001369324.1:p.Ile733Phe	missense
NC_000002.12:g.39012319T>A
NC_000002.11:g.39239460T>A
NG_007530.1:g.113145A>T
LRG_754:g.113145A>T
LRG_754t1:c.2197A>T	LRG_754p1:p.Ile733Phe
	Q07889:p.Ile733Phe

... more HGVS ... less HGVS

Protein change

I733F, I726F

Other names

p.I733F:ATC>TTC

Canonical SPDI

NC_000002.12:39012318:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA297205 UniProtKB: Q07889#VAR_030440 dbSNP: rs574088829 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SOS1		No evidence available	No evidence available	GRCh38 GRCh37	1681	1784

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 4, 2019	RCV000159127.5
Noonan syndrome 3	Likely pathogenic (1)	criteria provided, single submitter	Apr 17, 2017	RCV000587797.1
RASopathy	Pathogenic (1)	criteria provided, single submitter	Oct 4, 2022	RCV001233419.8
Noonan syndrome 4	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 22, 2022	RCV002051800.2
SOS1-related disorder	Pathogenic (1)	criteria provided, single submitter	Mar 8, 2023	RCV003407395.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 20, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209071.10 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015	Comment: p.Ile733Phe (ATC>TTC): c.2197 A>T in exon 14 of the SOS1 gene (NM_005633.3).The I733F missense mutation in the SOS1 gene has been reported previously in association … (more) p.Ile733Phe (ATC>TTC): c.2197 A>T in exon 14 of the SOS1 gene (NM_005633.3).The I733F missense mutation in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007). Functional studies have demonstrated that I773F is expected to increase RAS activation and lead to RAS GTPase cycling defects (Smith et al., 2013). The variant is found in NOONAN panel(s). (less)
Pathogenic (Mar 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SOS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004111061.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The SOS1 c.2197A>T variant is predicted to result in the amino acid substitution p.Ile733Phe. This variant has been reported in multiple individuals with Noonan syndrome … (more) The SOS1 c.2197A>T variant is predicted to result in the amino acid substitution p.Ile733Phe. This variant has been reported in multiple individuals with Noonan syndrome (see for example - Tartaglia et al 2007. PubMed ID: 17143282; Table S3 - Leach et al. 2018. PubMed ID: 2990780). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Smith et al. 2013. PubMed ID: 23487764). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
Pathogenic (Dec 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020778.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Apr 17, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Noonan syndrome 3 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698624.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (4) PubMed: 23487764‚ 21387466‚ 17143282‚ 20186801 Comment: Variant summary: The SOS1 c.2197A>T (p.Ile733Phe) variant causes a missense change involving the alteration of a conserved nucleotide. This variant is located in the Ras-like … (more) Variant summary: The SOS1 c.2197A>T (p.Ile733Phe) variant causes a missense change involving the alteration of a conserved nucleotide. This variant is located in the Ras-like guanine nucleotide exchange factor, N-terminal (IPR000651) (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). A functional study (Smith_PNAS_2013) showed that this variant increased pERK in a cell-culture model and increased RAS exchange activation by 2-3 fold. The variant of interest has not been found in a large, broad control population datasets of ExAC and gnomAD (0/121094 and 0/245906 control chrs tested, respectively). This variant was reported by multiple studies in patients with NS (Tartaglia_NatGenet_2007, Pierpont_AJMG_2010). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. (less)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 4 Affected status: yes Allele origin: germline	3billion Accession: SCV002318757.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (1) PubMed: 17143282 Comment: The variant has been previously reported as de novo in a similarly affected individual (PMID: 17143282). Same or different nucleotide change resulting in same amino … (more) The variant has been previously reported as de novo in a similarly affected individual (PMID: 17143282). Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040701, PMID:17143282). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.863>=0.75). A missense variant is a common mechanism associated with Noonan syndrome 4. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hepatomegaly (present) , Hypertrophic cardiomyopathy (present) , Postnatal cystic hygroma (present) , Pulmonic stenosis (present) , Aortic valve stenosis (present) , Primary dilated cardiomyopathy (present)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 4 Affected status: unknown Allele origin: germline	Genome-Nilou Lab Accession: SCV002763323.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Oct 04, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001406012.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 23487764‚ 17143282‚ 20186801‚ 21387466 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). Advanced modeling … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40701). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 17143282, 20186801, 21387466). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 733 of the SOS1 protein (p.Ile733Phe). (less)

Comment:

p.Ile733Phe (ATC>TTC): c.2197 A>T in exon 14 of the SOS1 gene (NM_005633.3).The I733F missense mutation in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007). Functional studies have demonstrated that I773F is expected to increase RAS activation and lead to RAS GTPase cycling defects (Smith et al., 2013). The variant is found in NOONAN panel(s).

Comment:

The SOS1 c.2197A>T variant is predicted to result in the amino acid substitution p.Ile733Phe. This variant has been reported in multiple individuals with Noonan syndrome (see for example - Tartaglia et al 2007. PubMed ID: 17143282; Table S3 - Leach et al. 2018. PubMed ID: 2990780). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Smith et al. 2013. PubMed ID: 23487764). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Comment:

Variant summary: The SOS1 c.2197A>T (p.Ile733Phe) variant causes a missense change involving the alteration of a conserved nucleotide. This variant is located in the Ras-like guanine nucleotide exchange factor, N-terminal (IPR000651) (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). A functional study (Smith_PNAS_2013) showed that this variant increased pERK in a cell-culture model and increased RAS exchange activation by 2-3 fold. The variant of interest has not been found in a large, broad control population datasets of ExAC and gnomAD (0/121094 and 0/245906 control chrs tested, respectively). This variant was reported by multiple studies in patients with NS (Tartaglia_NatGenet_2007, Pierpont_AJMG_2010). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.

Comment:

The variant has been previously reported as de novo in a similarly affected individual (PMID: 17143282). Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040701, PMID:17143282). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.863>=0.75). A missense variant is a common mechanism associated with Noonan syndrome 4. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40701). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 17143282, 20186801, 21387466). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 733 of the SOS1 protein (p.Ile733Phe).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NMR-based functional profiling of RASopathies and oncogenic RAS mutations.	Smith MJ	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23487764
SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.	Lepri F	Human mutation	2011	PMID: 21387466
Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome.	Pierpont EI	American journal of medical genetics. Part A	2010	PMID: 20186801
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.	Tartaglia M	Nature genetics	2007	PMID: 17143282

Text-mined citations for rs574088829 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005633.4(SOS1):c.2197A>T (p.Ile733Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs574088829 ...